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Rationale and objectivesThe role of human lung megakaryocytes in homeostasis and their dynamics in disease states remain unknown. We sought to investigate whether megakaryocyte/platelet gene signatures are altered in IPF.MethodsWe analyzed publicly available transcriptome datasets of lung tissue, bronchoalveolar lavage (BAL) cells, and peripheral whole blood from IPF patients and healthy controls. Enrichment of megakaryocyte and platelet gene signatures in those datasets were estimated using xCell, a novel computational method. Furthermore, we analyzed whether mean platelet volume (MPV) and platelet counts in peripheral blood are associated with lung transplant-free survival in our IPF cohort.ResultsIn lung tissue, megakaryocyte gene signature enrichment scores were significantly lower in IPF than in controls. In BAL cells, platelet gene signature enrichment scores were significantly lower in IPF than in controls, and lower platelet scores were associated with lower lung transplant-free survival in IPF. In contrast, in blood, megakaryocyte scores were significantly higher in IPF than in controls, and higher megakaryocyte scores were associated with lower disease progression-free survival in IPF. Furthermore, higher MPV was associated with lower transplant-free survival in our IPF cohort, independent of age, sex, forced vital capacity (FVC), and diffusing capacity of the lung for carbon monoxide (DLCO).ConclusionsIn IPF, megakaryocyte/platelet gene signatures were altered in a compartment-specific manner. Moreover, those signatures and MPV in blood were associated with important clinical outcomes such as transplant-free survival. These findings provide new insights into altered megakaryocyte/platelet biogenesis in IPF and suggest the potential utility of megakaryocyte/platelet-based biomarkers in IPF.

BackgroundAcute pulmonary embolism remains a significant cause of mortality and morbidity worldwide. Benefit of recently developed multidisciplinary PE response teams (PERT) with higher utilization of advanced therapies has not been established.MethodsTo evaluate patient-centered outcomes and cost-effectiveness of a multidisciplinary PERT we performed a retrospective analysis of 554 patients with acute PE at the university of Virginia between July 2014 and June 2015 (pre-PERT era) and between April 2017 through October 2018 (PERT era). Six-month survival, hospital length-of-stay (LOS), type of PE therapy, and in-hospital bleeding were assessed upon collected data.Results317 consecutive patients were treated for acute PE during an 18-month period following institution of a multidisciplinary PE program; for 120 patients PERT was activated (PA), the remaining 197 patients with acute PE were considered as a separate, contemporary group (NPA). The historical, comparator cohort (PP) was composed of 237 patients. These 3 groups were similar in terms of baseline demographics, comorbidities and risk, as assessed by the Pulmonary Embolism Severity Index (PESI). Patients in the historical cohort demonstrated worsened survival when compared with patients treated during the PERT era. During the PERT era no statistically significant difference in survival was observed in the PA group when compared to the NPA group despite significantly higher severity of illness among PA patients. Hospital LOS was not different in the PA group when compared to either the NPA or PP group. Hospital costs did not differ among the 3 cohorts. 30-day re-admission rates were significantly lower during the PERT era. Rates of advanced therapies were significantly higher during the PERT era (9.1% vs. 2%) and were concentrated in the PA group (21.7% vs. 1.5%) without any significant rise in in-hospital bleeding complications.ConclusionsAt our institution, all-cause mortality in patients with acute PE has significantly and durably decreased with the adoption of a PERT program without incurring additional hospital costs or protracting hospital LOS. Our data suggest that the adoption of a multidisciplinary approach at some institutions may provide benefit to select patients with acute PE.

Additional file 2: Supplemental Figure 2. Prevalence of non-PE related mechanical ventilation requirement and shock among patients among (A) pre-PERT and PERT-era patients and (B) Pert activated and non-PERT activated subjects in the PERT era; MV, mechanical ventilation, shock is defined as hypotension requiring vasopressor medication. * p

Additional file 3: Supplementary Table 1 Performed risk assessment and severity of PE. Abbreviations: PP; pre-PERT; PA, PERT alerted; NPA, Non-PERT alerted; BNP, Brain natriuretic peptide; TTE, transthoracic echocardiogram; RV, right ventricle; CT, computer tomography. a) assessment within 12 h of pulmonary embolism diagnosis, b) positive RV strain by biomarkers was determined as troponin> 0.02 ng/mL, and/or BNP > 155 pg/mL; c) RV strain on CT imaging was determined as RV/LV ration (ratio of right ventricular to left ventricular diameter ration of > 0.9). P value calculated by Chi Square test.

Additional file 1: Supplemental Figure 1. Distribution of 2019 ESC risk categories among the 3 groups. ESC, European Society of Cardiology.

BACKGROUND: The primary objective was to provide proof of concept of conducting thoracic surgical simulation in a low-middle income country (LMIC). Secondary objectives were to accelerate general thoracic surgery skills acquisition by general surgery residents and sustain simulation surgery teaching through a website, simulation models, and teaching of local faculty. METHODS: Five training models were created for use in a LMIC setting and implemented during on-site courses with Rwandan general surgery residents. A website was created as a supplement to the on-site teaching. All participants completed pre- and post-simulation course knowledge assessment and feedback/confidence surveys. Descriptive and univariate analyses were performed on participants’ responses. RESULTS: Twenty-three participants completed the simulation course. Eight (35%) had previous training with the course models. All training levels were represented. Participants reported higher rates of meaningful confidence – defined as moderate to complete on a Likert scale – for all simulated thoracic procedures (p

Studies in human populations have shown a significant correlation between procollagen C-endopeptidase enhancer protein 2 (PCPE2) single nucleotide polymorphisms and plasma HDL cholesterol concentrations. PCPE2, a 52-kDa glycoprotein located in the extracellular matrix, enhances the cleavage of C-terminal procollagen by bone morphogenetic protein 1 (BMP1). Our studies here focused on investigating the basis for the elevated concentration of enlarged plasma HDL in PCPE2-deficient mice to determine whether they protected against diet-induced atherosclerosis. PCPE2-deficient mice were crossed with LDL receptor-deficient mice to obtain LDLr(-/-), PCPE2(-/-) mice, which had elevated HDL levels compared with LDLr(-/-) mice with similar LDL concentrations. We found that LDLr(-/-), PCPE2(-/-) mice had significantly more neutral lipid and CD68+ infiltration in the aortic root than LDLr(-/-) mice. Surprisingly, in light of their elevated HDL levels, the extent of aortic lipid deposition in LDLr(-/-), PCPE2(-/-) mice was similar to that reported for LDLr(-/-), apoA-I(-/-) mice, which lack any apoA-I/HDL. Furthermore, LDLr(-/-), PCPE2(-/-) mice had reduced HDL apoA-I fractional clearance and macrophage to fecal reverse cholesterol transport rates compared with LDLr(-/-) mice, despite a 2-fold increase in liver SR-BI expression. PCPE2 was shown to enhance SR-BI function by increasing the rate of HDL-associated cholesteryl ester uptake, possibly by optimizing SR-BI localization and/or conformation. We conclude that PCPE2 is atheroprotective and an important component of the reverse cholesterol transport HDL system.

Epidemiological studies have shown an inverse correlation between plasma high density lipoprotein (HDL) concentrations and cardiovascular disease risk. At variance with these observations, clinical trials that significantly raised plasma HDL-C levels did not have improved clinical outcomes, emphasizing the importance of understanding HDL function. Recently, a significant correlation has been reported between human procollagen c-endopeptidase enhancer protein 2 (PCPE2) single nucleotide polymorphisms and HDL. PCPE2, a 52 kDa glycoprotein found in the extracellular matrix enhances cleavage of C-terminal procollagen by bone morphogenetic protein 1. Mice lacking PCPE2 have elevated concentrations of enlarged plasma HDL, a phenomenon associated with defective cholesterol efflux. HDL synthesis depends on ABCA1-mediated lipid efflux to lipid-poor apoA-I balanced by cholesterol uptake through hepatic scavenger receptor class B type I (SR-BI). Our studies focused on investigating if the elevated concentration of enlarged plasma HDL in PCPE2 deficient mice was atheroprotective. PCPE2 deficient mice were crossed with LDLr -/- mice (SKO) giving LDLr -/- , PCPE2 -/- (DKO) mice that had elevated HDL levels compared to SKO mice. Despite elevated HDL levels, we found that DKO mice had significantly more lipid and CD68+ infiltration into the aortic root, similar to that reported for LDLr -/- , apoA-I -/- mice that lack plasma apoA-I/HDL. Furthermore, DKO mice showed reduced HDL apoA-I fractional clearance and reverse cholesterol transport rates compared to SKO mice suggesting PCPE2 plays a significant role in HDL remodeling and/or cholesterol uptake by the liver. To test the effect of PCPE2 on SR-BI function we incubated 3 H-cholesteryl ether ( 3 H-CE) enriched HDL from SKO and DKO mice with CHO cells overexpressing PCPE2. Compared to CHO control cells, overexpression of PCPE2 increased 3 H-CE HDL uptake that was independent of HDL particle origin. Western Blot analysis showed no difference in SR-BI expression between control and PCPE2 transfected cells, suggesting that PCPE2 enhanced SR-BI function and promoted HDL cholesterol ester uptake. We conclude that PCPE2 is atheroprotective and an essential component of the reverse cholesterol transport system.

Cytokines/chemokines and their receptors have been an important consideration when investigating the role of inflammation in atherosclerosis. In humans and animal models, monocyte recruitment and accumulation within the artery wall occurs in response to elevated plasma cholesterol levels. To mimic this process in a mouse model of atherosclerosis, our lab has utilized the LDLr-/-, ApoA-I-/- double knockout mouse. Our studies have shown that LDLr-/-, ApoA-I-/- mice have increased immune cell mobilization driving the progression of atherosclerosis when compared to LDLr-/- mice, and that treating mice with frequent, low doses (200 μg) of subcutaneous administered lipid-free apoA-I or rHDL reverses the atherogenic process. Based on these studies we wanted to investigate which inflammatory pathways were most affected by apoA-I treatment. To do this, we carried out RT-PCR to obtain the relative mRNA abundance on 40 different markers of inflammation in two genotypes of atherogenic diet fed mice. Each genotype of mice was divided into two subsets. One subset was fed an atherogenic diet for 12 weeks while the other subset received 12 weeks of diet and subcutaneous injections of 200 μg of apoA-I for the last 6 weeks of the study. Spleen was isolated from all animals and their inflammatory gene mRNA expression examined. Most significantly both genotypes showed a large decrease in IL-3 mRNA expression but also showed a significant increase in CD163 mRNA expression with apoA-I treatment. Decrease in splenic IL-3 expression is a significant mediator of inflammation regression because of the role IL-3 plays in monocyte production inside the spleen. Other investigators have shown that myeloid cells reserved in the spleen give rise to monocytes in an IL-3 rich environment. IL-3 develops and maintains circulating monocytes, which may accumulate in the arteries during atherosclerosis. This suggests apoA-I treatment affects IL-3 levels in the spleen, and thus the amount of monocytes in circulation. An increase in CD163 mRNA expression in the spleen implies higher accumulation of monocytes inside the spleen, and out of circulation. This suggests that apoA-1 treatment can decrease the amount of monocytes in the arteries, which can be a result of reverse in the atherogenic process.